Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors

References

• World Health Organization [Internet]. Geneva, Switzerland; [cited 2019 June 2]. Available from: http://www.who.int/gho/ncd/risk_factors/overweight/en/
   Google Scholar
• Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313(22):2263–2273.
   PubMed Web of Science ®Google Scholar
• Seravalle G, Grassi G. Obesity and hypertension. Pharmacol Res. 2017;122:1–7.
   PubMed Web of Science ®Google Scholar
• Lu Y, Hajifathalian K, Ezzati M, et al. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1.8 million participants. Lancet. 2014;383(9921):970–983.
   PubMed Web of Science ®Google Scholar
• Nakano R, Takebe N, Ono M, et al. Involvement of oxidative stress in atherosclerosis development in subjects with sarcopenic obesity. Obes Sci Pract. 2017;3:212–218.
   PubMed Web of Science ®Google Scholar
• Dyck L, Lynch L. Cancer, obesity and immunometabolism-Connecting the dots. Cancer Lett. 2018;417:11–20.
   PubMed Web of Science ®Google Scholar
• Data was obtained from the World Health Organization [Internet]. Geneva, Switzerland; [cited 2019 June 2]. Available from: http://www.who.int/diabetes/global-report/en/
   Google Scholar
• Wakil SJ, Stoops JK, Joshi VC, et al. Fatty acid synthesis and its regulation. Annu Rev Biochem. 1983;52:537–579.
   PubMed Web of Science ®Google Scholar
• Munday MR, Hemingway CJ. The regulation of acetyl-CoA carboxylase – a potential target for the action of hypolipidemic agents. Advan Enzyme Regul. 1999;39:205–234.
   PubMedGoogle Scholar
• Barber MC, Price NT, Travers MT, et al. Structure and regulation of acetyl-CoA carboxylase genes of metazoa. Biochim Biophys Acta. 2005;1733:1–28.
   PubMed Web of Science ®Google Scholar
• Tong L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci. 2005;62:1784–1803.
   PubMed Web of Science ®Google Scholar
• Abu-Elheiga L, Brinkley WR, Zhong L, et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci USA. 2000;97:1444–1449.
   PubMed Web of Science ®Google Scholar
• Munday MR, Campbell DG, Carling D, et al. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur J Biochem. 1988;175:331–338.
   PubMedGoogle Scholar
• Oh SY, Park SK, Kim JW, et al. Acetyl-CoA carboxylase β gene is regulated by sterol regulatory element-binding protein-1 in liver. J Biol Chem. 2003;278:28410–28417.
   PubMed Web of Science ®Google Scholar
• Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell. 2005;120:261–273.
   PubMed Web of Science ®Google Scholar
• Dentin R, Girard J, Postic C, et al. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 2005;87:81–86.
   PubMed Web of Science ®Google Scholar
• Kaushik VK, Kavana M, Volz JM, et al. Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. Biochim Biophys Acta. 2009;1794:961–967.
   PubMed Web of Science ®Google Scholar
• Cho YS, Lee JI, Shin D, et al. Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. Biochem Biophys Res Commun. 2010;391:187–192.
   PubMed Web of Science ®Google Scholar
• Mao J, DeMayo FJ, Li H, et al. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci USA. 2006;103:8552–8557.
   PubMed Web of Science ®Google Scholar
• Mao J, Yang T, Gu Z, et al. aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proc Natl Acad Sci USA. 2009;106:17576–17581.
   PubMed Web of Science ®Google Scholar
• Abu-Elheiga L, Matzuk MM, Kordari P, et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci USA. 2005;102:12011–12016.
   PubMed Web of Science ®Google Scholar
• Oh W, Abu-Elheiga L, Kordari P, et al. Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice. Proc Natl Acad Sci USA. 2004;102:1384–1389.
   Web of Science ®Google Scholar
• Abu-Elheiga L, Matzuk MM, Abo-Hashema KAH. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-coa carboxylase 2. Science. 2001;291:2613–2616.
   PubMed Web of Science ®Google Scholar
• Abu-Elheiga L, Oh W, Kordari P, et al. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat high-carbohydrate diets. Proc Natl Acad Sci USA. 2003;100:10207–10212.
   PubMed Web of Science ®Google Scholar
• Ronnebaum SM, Joseph JW, Ilkayeva O, et al. Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J Biol Chem. 2008;283:14248–14256.
   PubMed Web of Science ®Google Scholar
• Glien M, Haschke G, Schroeter K, et al. Stimulation of fat oxidation, but no sustained reduction of hepatic lipids by prolonged pharmacological inhibition of acetyl CoA carboxylase. Horm Metab Res. 2011;43:601–606.
   PubMed Web of Science ®Google Scholar
• Corbett JW, Harwood J, James H, et al. Inhibitors of mammalian acetyl-CoA carboxylase. Recent Pat Cardiovasc Drug Discov. 2007;2(3):162–180.
   PubMedGoogle Scholar
• Gerth K, Bedorf N, Irschik H, et al. The soraphens: A family of novel antifungal compounds froms orangium cellulosum (myxobacteria). J Antibiot (Tokyo). 1993;47:23–31.
   Google Scholar
• Vahlensieck HF, Pridzun L, Reichenbach H, et al. Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polketide fungicide soraphen A. Curr Genet. 1994;25:95–100.
   PubMed Web of Science ®Google Scholar
• Shen Y, Volrath SL, Weatherly SC, et al. A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme a carboxylase by Soraphen A, a macrocyclic polyketide natural product. Mol Cell. 2004;16:881–891.
   PubMed Web of Science ®Google Scholar
• Weatherly SC, Volrath SL, Elich TD, et al. Expression and characterization of recombinant fungal acetyl-CoA carboxylase and isolation of a soraphen-binding domain. Biochem J. 2004;380(Pt 1):105–110.
   PubMedGoogle Scholar
• Schreurs M, Van Dijk TH, Gerding A, et al. An inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet. Diabetes Obesity Metab. 2009;11:987–991.
   PubMed Web of Science ®Google Scholar
• Jump DB, Torres-Gonzalez M, Olson LK, et al. Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation. Biochem Pharmacol. 2011;81:649–660.
   PubMed Web of Science ®Google Scholar
• Beckers A, Organe S, Timmermans L, et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 2007;67:8180–8187.
   PubMed Web of Science ®Google Scholar
• Vincent G, Mansfield DJ, Vors JP, et al. Studies toward soraphen A: an aldol-metathesis avenue to the macrocyclic framework. Org Lett. 2006;8(13):2791–2794.
   PubMed Web of Science ®Google Scholar
• Trost BM, Sieber JD, Qian W, et al. Asymmetric total synthesis of soraphen A: A flexible alkyne strategy. Angew Chem Int Ed. 2009;48:5478–5481.
   PubMed Web of Science ®Google Scholar
• Lu HH, Raja A, Franke R, et al. Synthesis and biological evaluation of Paleo-Soraphens. Angew Chem Int Ed. 2013;52:13549–13552.
   PubMed Web of Science ®Google Scholar
• Lu HH, Hinkelmann B, Tautz T, et al. Paleo-Soraphens: chemical total syntheses and biological studies. Org Biomol Chem. 2015 Aug 07;13(29):8029−8036.
   Web of Science ®Google Scholar
• Canterbury DP, Scott KEN, Kubo O, et al. Synthesis of C11-desmethoxy soraphen A1α: A natural product analogue that inhibits acetyl-CoA carboxylase. ACS Med Chem Lett. 2013;4:1244−1248.
   PubMed Web of Science ®Google Scholar
• Stoiber K, Nagło O, Pernpeintner C, et al. Targeting de novo lipogenesis as a novel approach in anti-cancer therapy. Br J Cancer. 2018;118(1):1–9.
   PubMed Web of Science ®Google Scholar
• Corominas-Faja B, Cuyàs E, Gumuzio J, et al. Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells. Oncotarget. 2014;5(18):8306–8316.
   PubMedGoogle Scholar
• Rysman E, Brusselmans K, Scheys K, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 2010;70(20):8117–8126.
   PubMed Web of Science ®Google Scholar
• Harwood HJ, Petras SF, Shelly LD, et al. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem. 2003;278:37099–37111.
   PubMed Web of Science ®Google Scholar
• Zhang H, Tweel B, Li J, et al. Crystal structure of the carboxytransferase domain of acetyl-CoA carboxylase in complex with CP-640186. Structure. 2004;12:1683−1691.
   PubMed Web of Science ®Google Scholar
• Madauss KP, Burkhart WA, Consler TG, et al. The human ACC2 CT-domain C-terminus is required for full functionality and has a novel twist. Acta Cryst. 2009;D65:449–461.
   Google Scholar
• Zhang H, Yang Z, Shen Y, et al. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science. 2003;299:2064–2067.
   PubMed Web of Science ®Google Scholar
• Chonan T, Oi T, Yamamoto D, et al. (4-Piperidinyl)-piperazine: A new platform for acetyl-CoA carboxylase inhibitors. Bioorg Med Chem Lett. 2009;19:6645–6648.
   PubMed Web of Science ®Google Scholar
• Chonan T, Tanaka H, Yamamoto D, et al. Design and synthesis of disubstituted (4-piperidinyl)-piperazine derivatives as potent acetyl-CoA carboxylase inhibitors. Bioorg Med Chem Lett. 2010;20:3965–3968.
   PubMed Web of Science ®Google Scholar
• Chonan T, Wakasugi D, Yamamoto D, et al. Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group. Bioorg Med Chem. 2011;19:1580–1593.
   PubMed Web of Science ®Google Scholar
• Vyas VK, Dabasia M, Qureshi G, et al. Molecular modeling study for the design of novel Acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations. J Biomol Struct Dyn. 2017;35:2003–2015.
   PubMed Web of Science ®Google Scholar
• Yamashita T, Kamata M, Endo S, et al. Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors. Bioorg Med Chem Lett. 2011;21:6314–6318.
   PubMed Web of Science ®Google Scholar
• Kamata M, Yamashita T, Kina A, et al. Design, synthesis, and structure–activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors. Bioorg Med Chem Lett. 2012;22:3643–3647.
   PubMed Web of Science ®Google Scholar
• Kamata M, Yamashita T, Kina A, et al. Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoAvcarboxylase inhibitors. Bioorg Med Chem Lett. 2012;22:4769–4772.
   PubMed Web of Science ®Google Scholar
• Corbett JW, Freeman-Cook KD, Elliott R, et al. Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg Med Chem Lett. 2010;20:2383–2388.
   PubMedGoogle Scholar
• Freeman-Cook KD, Amor P, Bader S, et al. Maximizing lipophilic efficiency: the use of free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase. J Med Chem. 2012;55:935−942.
   PubMed Web of Science ®Google Scholar
• Bagley SW, Southers JA, Cabral S, et al. Synthesis of 7-Oxo-dihydrospiro [indazole-5,4′-piperidine] acetyl-CoA carboxylase inhibitors. J Org Chem. 2012;77:1497−1506.
   PubMed Web of Science ®Google Scholar
• Huard K, Bagley SW, Menhaji-Klotz E, et al. Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors. J Org Chem. 2012;77:10050−10057.
   PubMed Web of Science ®Google Scholar
• Griffith DA, Dow RL, Huard K, et al. Spirolactam-based Acetyl-CoA Carboxylase inhibitors: toward improved metabolic stability of a chromanone lead structure. J Med Chem. 2013;56:7110−7119.
   PubMed Web of Science ®Google Scholar
• Griffith DA, Kung DW, Esler WP, et al. Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes. J Med Chem. 2014;57:10512–10526.
   PubMed Web of Science ®Google Scholar
• Kim CW, Addy C, Kusunoki J, et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 2017;26:394–406 e6.
   PubMed Web of Science ®Google Scholar
• Bergman A, Gonzalez SC, Tarabar S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of a liver-targeting ACC inhibitor (PF-05221304) following single and multiple oral doses. J Hepatol. 2018;68(Suppl 1):S582.
   Google Scholar
• Esler W, Ross T, Bergman A, et al. Partial inhibition of de novo lipogenesis with the acetyl-CoA carboxylase inhibitor PF-05221304 does not increase circulating triglycerides in humans and is sufficient to lower steatosis in rats. J Hepatol. 2019;70(1):e69.
   Web of Science ®Google Scholar
• Parker RA, Kariya T, Grisar JM, et al. 5-(tetradecyloxy)-2-furancarboxylic acid and related hypolipidemic fatty acid-like alkyloxyarylcarboxylic acids. J Med Chem. 1977;20:781–791.
   PubMed Web of Science ®Google Scholar
• Harris RA, McCune SA. 5-(tetradecyloxy)-2-furoic acid. Methods Enzymol. 1981;72:552–559.
   PubMedGoogle Scholar
• Hunt DW, Winters GC, Brownsey RW, et al. Inhibition of sebum production with the acetyl coenzyme a carboxylase inhibitor olumacostat glasaretil. J Invest Dermatol. 2017;137:1415–1423.
   PubMed Web of Science ®Google Scholar
• Melnik BC. Olumacostat Glasaretil, a promising topical sebum-suppressing agent that affects all major pathogenic factors of acne vulgaris. J Invest Dermatol. 2017;137:1405–1408.
   PubMed Web of Science ®Google Scholar
• Melnik BC. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update. Clin Cosmet Investig Dermatol. 2015;8:371–388.
   PubMed Web of Science ®Google Scholar
• Bissonnette R, Poulin Y, Drew J, et al. Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: A phase IIa, multicenter, randomized, vehicle-controlled study. J Am Acad Dermatol. 2017;76:33–39.
   PubMed Web of Science ®Google Scholar
• Zouboulis CC, Dessinioti C, Tsatsou F, et al. Anti-acne drugs in phase 1 and 2 clinical trials. Expert Opin Investig Drugs. 2017;26(7):813–823.
   PubMed Web of Science ®Google Scholar
• Harrimana G, Greenwood J, Bhat S, et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci USA. 2016;113:E1796–E1805.
   PubMed Web of Science ®Google Scholar
• Bourbeau MP, Bartberger MD. Recent advances in the development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease. J Med Chem. 2015;58(2):525–536.
   PubMed Web of Science ®Google Scholar
• Stiede K, Miao W, Blanchette HS, et al. Acetyl-Coenzyme A Carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology. 2017;66:324–334.
   PubMed Web of Science ®Google Scholar
• Loomba R, Kayali Z, Noureddin M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;154.
   Web of Science ®Google Scholar
• Lawitz EJ, Coste A, Poordad F, et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2018 Apr 26. 16:1983–1991.e3.
   PubMed Web of Science ®Google Scholar
• Harrison S, Noureddin M, Herring R, et al. Preliminary efficacy and safety of acetyl-CoA carboxylase inhibitor GS-0976 in patients with compensated cirrhosis due to NASH. Gastroenterology. 2018;154(6):S–1166.
   Web of Science ®Google Scholar
• Mantry P, Kayali Z, Noureddin M, et al. Characterization of changes in lipoprotein profiles of patients with nonalcoholic steatohepatitis treated with the acetyl-CoA carboxylase inhibitor GS-0976. J Hepatol. 2018;68:S583–S584.
   Web of Science ®Google Scholar
• Burton JD, Gronwald JW, Somers DA, et al. Inhibition of plant acetyl-coenzyme a carboxylase by the herbicides sethoxydim and haloxyfop. Biochem Biophys Res Commun. 1987;148(3):1039–1044.
   PubMed Web of Science ®Google Scholar
• Burton JD, Gronwald JW, Keith RA, et al. Kinetics of inhibition of acetyl-coenzyme A carboxylase by sethoxydim and haloxyfop. Pestic Biochem Physiol. 1991;39(2):100–109.
   Web of Science ®Google Scholar
• Kemal C, Casida JE Coenzyme a esters of 2-aryloxyphenoxypropionate herbicides and 2-arylpropionate antiinflammatory drugs are potent and stereoselective inhibitors of rat liver acetyl-CoA carboxylase. Life Sci. 1992;50(7):533–540.
   PubMed Web of Science ®Google Scholar
• Zhang H, Tweel B, Tong L, et al. Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop. Proc Natl Acad Sci USA. 2004;101(16):5910–5915.
   PubMed Web of Science ®Google Scholar
• Xiang S, Callaghan MM. A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim. Proc Natl Acad Sci USA. 2009;106(49):20723–20727.
   PubMed Web of Science ®Google Scholar
• Linda PC, Kim YS, Tong L, et al. Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by pinoxaden. Proc Natl Acad Sci USA. 2010;107(51):22072–22077.
   PubMed Web of Science ®Google Scholar
• Gu YG, Weitzberg M, Clark RF, et al. Synthesis and structure-activity relationships of N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors. J Med Chem. 2006;49:3770–3773.
   PubMed Web of Science ®Google Scholar
• Clark RF, Zhang T, Xin Z, et al. Structure–activity relationships for a novel series of thiazolyl phenyl ether derivatives exhibiting potent and selective acetyl-CoA carboxylase 2 inhibitory activity. Bioorg Med Chem Lett. 2006;16:6078–6081.
   PubMed Web of Science ®Google Scholar
• Gu YG, Weitzberg M, Clark RF, et al. N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-CoA carboxylase inhibitors improvement of cardiovascular and neurological liabilities via structural modifications. J Med Chem. 2007;50:1078–1082.
   PubMed Web of Science ®Google Scholar
• Nishiura Y, Matsumura A, Kobayashi N, et al. Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy. Bioorg Med Chem Lett. 2018;28:2498–2503.
   PubMed Web of Science ®Google Scholar
• Mizojiri R, Asano M, Tomita D, et al. Discovery of novel selective Acetyl-CoA carboxylase (ACC) 1 inhibitors. J Med Chem. 2018;61:1098−1117.
   PubMedGoogle Scholar
• Bengtsson C, Blaho S, Saitton DB, et al. Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats. Bioorg Med Chem. 2011;19:3039–3053.
   PubMed Web of Science ®Google Scholar
• Keil S, Müller M, Zoller G, et al. Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation. J Med Chem. 2010;53:8679–8687.
   PubMedGoogle Scholar
• Bourbeau MP, Siegmund A, Allen JG, et al. Piperazine oxadiazole inhibitors of acetyl-CoA carboxylase. J Med Chem. 2013;56:10132−10141.
   PubMed Web of Science ®Google Scholar
• Okazaki S, Noguchi-Yachide T, Sakai T, et al. Discovery of N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl) acetamides as novel acetyl-CoA carboxylase 2 (ACC2) inhibitors with peroxisome proliferator-activated receptor α/δ (PPAR α/δ) dual agonistic activity. Bioorg Med Chem. 2016;24:5258–5269.
   PubMed Web of Science ®Google Scholar
• Esler WP, Tesz GJ, Hellerstein MK, et al. Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition. Sci Transl Med. 2019;11:eaau8465.
   PubMed Web of Science ®Google Scholar
• Zhan Y, Ginanni N, Tota MR, et al. Control of cell growth and survival by enzymes of the fatty acid synthesis pathway in HCT-116 colon cancer cells. Clin Cancer Res. 2008;14:5735–5742.
   PubMed Web of Science ®Google Scholar
• Chajes V, Cambot M, Moreau K, et al. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res. 2006;66:5287–5294.
   PubMed Web of Science ®Google Scholar
• Brusselmans K, Schrijver ED, Verhoeven G, et al. RNA interference-mediated silencing of the acetyl-CoA carboxylase-a gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 2005;65:6719–6725.
   PubMed Web of Science ®Google Scholar
• Petrova E, Scholz A, Paul J, et al. Acetyl-CoA carboxylase inhibitors attenuate WNT and Hedgehog signaling and suppress pancreatic tumor growth. Oncotarget. 2017;8:48660–48670.
   PubMedGoogle Scholar
• Jones JEC, Esler WP, Patel R, et al. Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) reduces proliferation and de novo lipogenesis of EGFRvIII human glioblastoma cells. PLoS ONE. 2017;12(1):e0169566.
   PubMed Web of Science ®Google Scholar
• Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr. 2008;28:253–272.
   PubMed Web of Science ®Google Scholar
• Harwood HJ. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opin Ther Targets. 2005;9(2):267–281.
   PubMed Web of Science ®Google Scholar
• Currie E, Schulze A, Zechner R. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18:153–161.
   PubMed Web of Science ®Google Scholar
• Esler WP, Bence KK. Metabolic targets in nonalcoholic fatty liver disease. Cell Mol Gastroenterol Hepatol. 2019 Apr 18. 8:247–267
   PubMed Web of Science ®Google Scholar
• Kim KH, Lee MS. Pathogenesis of nonalcoholic steatohepatitis and hormone-based therapeutic approaches. Front Endocrinol. 2018;9:485.
   PubMed Web of Science ®Google Scholar
• Yu XX, Murray SF, Pandey SK, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 2005;42:362–371.
   PubMed Web of Science ®Google Scholar
• Choi CS, Savage DB, Kulkarni A, et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses dietinduced hepatic steatosis and insulin resistance. J Biol Chem. 2007;282:22678–22688.
   PubMed Web of Science ®Google Scholar
• Liu X, Xue R, Ji L, et al. Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction. Biochem Biophys Res Commun. 2014;450(1):117–123.
   PubMed Web of Science ®Google Scholar
• Cariou B. The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis Le récepteur nucléaire FXR (farnesoid X receptor): une nouvelle cible moléculaire pour le traitement de la NASH. Diabetes Metab. 2008;34(6):685–691.
   PubMedGoogle Scholar